title: The novel anti-inflammatory agent VA694, endowed with both NO-releasing and COX2-selective inhibiting properties, exhibits NO-mediated positive effects on blood pressure, coronary flow and endothelium in an experimental model of hypertension and endothelial dysfunction.
abstract: Selective cyclooxygenase 2 (COX2) inhibitors (COXIBs) are effective anti-inflammatory and analgesic drugs with improved gastrointestinal (GI) safety compared to nonselective nonsteroidal anti-inflammatory drugs known as traditional (tNSAIDs). However, their use is associated with a cardiovascular (CV) hazard (i.e. increased incidence of thrombotic events and hypertension) due to the inhibition of COX2-dependent vascular prostacyclin. Aiming to design COX2-selective inhibitors with improved CV safety, new NO-releasing COXIBs (NO-COXIBs) have been developed. In these hybrid drugs, the NO-mediated CV effects are expected to compensate for the COXIB-mediated inhibition of prostacyclin. This study evaluates the potential CV beneficial effects of VA694, a promising NO-COXIB, the anti-inflammatory effects of which have been previously characterized in several in vitro and in vivo experimental models. When incubated in hepatic homogenate, VA694 acted as a slow NO-donor. Moreover, it caused NO-mediated relaxant effects in the vascular smooth muscle. The chronic oral administration of VA694 to young spontaneously hypertensive rats (SHRs) significantly slowed down the age-related development of hypertension and was associated with increased plasma levels of nitrates, stable end-metabolites of NO. Furthermore, a significant improvement of coronary flow and a significant reduction of endothelial dysfunction were observed in SHRs submitted to chronic administration of VA694. In conclusion, VA694 is a promising COX2-inhibiting hybrid drug, showing NO releasing properties which may mitigate the CV deleterious effects associated with the COX2-inhibition.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno, 6, I-56126 Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Martelli
authors.forename: L
authors.initials: L
authors.lastname: Testai
authors.forename: M
authors.initials: M
authors.lastname: Anzini
authors.forename: A
authors.initials: A
authors.lastname: Cappelli
authors.forename: A
authors.initials: A
authors.lastname: Di Capua
authors.forename: M
authors.initials: M
authors.lastname: Biava
authors.forename: G
authors.initials: G
authors.lastname: Poce
authors.forename: S
authors.initials: S
authors.lastname: Consalvi
authors.forename: A
authors.initials: A
authors.lastname: Giordani
authors.forename: G
authors.initials: G
authors.lastname: Caselli
authors.forename: L
authors.initials: L
authors.lastname: Rovati
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
authors.forename: P
authors.initials: P
authors.lastname: Patrignani
authors.forename: L
authors.initials: L
authors.lastname: Sautebin
authors.forename: M C
authors.initials: MC
authors.lastname: Breschi
authors.forename: V
authors.initials: V
authors.lastname: Calderone
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004727:Endothelium / Q000187:drug effects* / Q000473:pathology; D045462:Endothelium-Dependent Relaxing Factors / Q000008:administration & dosage* / Q000494:pharmacology; D006973:Hypertension / Q000097:blood / Q000188:drug therapy*; D008297:Male; D009566:Nitrates / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000494:pharmacology; D009573:Nitrites / Q000097:blood; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D045462:Endothelium-Dependent Relaxing Factors; D009566:Nitrates; D009573:Nitrites; D011758:Pyrroles; C000608356:VA 694; D009569:Nitric Oxide
keywords: 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one; 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethanol; 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethanol (PubChem CID: 56929591); 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethyl nitrate; 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethyl nitrate (PubChem CID: 56929588); ACh; ANOVA; APPROVe; Adenomatous Polyp PRevention On Vioxx study; Anti-inflammatory drugs; BP; CINOD; COX(2); COX(2)-inhibitors; COX(2)-selective inhibitors; COX-inhibiting nitric oxide donor; COXIBs; CV; DMSO; Endothelial dysfunction; GC; HR; Hypertension; IL-1β; LVDP; NA; NO; NO-naproxen (PubChem CID: 9884642); NR; NSAIDs; Nitric oxide-releasing drugs; ODQ; Pharmacodynamic hybrids; RB; SBP; SEM; SHRs; SNP; VA692; VA694; VIGOR; Vioxx Gastrointestinal Outcome studies; acetylcholine; analysis of variance; blood pressure; cardiovascular; cyclooxygenase-2; dimethylsulphoxide; guanylate cyclase; heart rate; interleukine-1β; left ventricular developed pressure; nitrate reductase bars; nitric oxide; non-steroidal anti-inflammatory drugs; noradrenaline; resuspending buffer; sodium nitroprusside; spontaneously hypertensive rats; standard error of the mean; systolic blood pressure; tNSAIDs; traditional non-steroidal anti-inflammatory drugs